1,2-annelated quinoline derivatives

ABSTRACT

This invention concerns compounds of formula 
                 
 
the pharmaceutically acceptable acid addition salts and the stereochemically isomeric forms thereof, wherein ═X 1 —X 2 —X 3 — is a trivalent radical,; &gt;Y 1 —Y 2 — is a trivalent radical; r and s are each independently 0, 1, 2, 3, 4 or 5; t is 0, 1, 2 or 3; each R 1  and R 2  are independently hydroxy, halo, cyano, C 1-6 alkyl, trihalomethyl, trihalomethoxy, C 2-6 alkenyl, C 1-6 alkyloxy, hydroxyC 1-6 alkyloxy, C 1-6 alkylthio, C 1-6 alkyloxyC 1-6 alkyloxy, C 1-6 alkyloxycarbonyl, aminoC 1-6 alkyloxy, mono- or di(C 1-6 alkyl)amino, mono- or di(C 1-6 alkylaminoC 1-6 alkyloxy, aryl, arylC 1-6 alkyl, aryloxy or arylC 1-6 alkyloxy, hydroxycarbonyl, C 1-6 alkyloxycarbonyl; or two R 1  or R 2  on adjacent positions form together a bivalent radical; R 3  is hydrogen, halo, C 1-6 alkyl, cyano, haloC 1-6 alkyl, hydroxyC 1-6 alkyl, cyanoC 1-6 alkyl, aminoC 1-6 alkyl, C 1-6 alkyloxyC 1-6 alkyl, C 1-6 alkylthio-C 1-6 alkyl, aminocarbonylC 1-6 alkyl, hydroxycarbonyl, hydroxycarbonylC 1-6 alkyl, C 1-6 alkyoxycarbonylC 1-6 alkyl, C 1-6 alkylcarbonylC 1-6 alkyl, C 1-6 alkyloxycarbonyl, aryl, arylC 1-6 alkyloxyC 1-6 alkyl, mono- or di(C 1-6 alkyl)aminoC 1-6 alkyl, or a radical of formula —O—R 10 , —S—R 10  or —NR 11 R 12 ; R 4  is an optionally substituted imidazolyl; aryl is an optionally substituted phenyl or naphthalenyl; having farnesyl transferase and geranylgeranyl transferase inhibiting activity; their preparation, compositions containing them and their use as a medicine.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a divisional of 09/868,992, filed Aug. 29, 2001, nowU.S. Pat. No. 6,458,800, which is a National Stage application under 35U.S.C. § 371 of PCT/EP99/10214 filed Dec. 17, 1999, which claimspriority from EP 98204444.8, filed Dec. 23, 1998, the entirety of whichis incorporated herein by reference.

The present invention is concerned with novel 1,2-annelated quinolinederivatives, the preparation thereof, pharmaceutical compositionscomprising said novel compounds and the use of these compounds as amedicine as well as methods of treatment by administering saidcompounds.

Oncogenes frequently encode protein components of signal transductionpathways which lead to stimulation of cell growth and mitogenesis.Oncogene expression in cultured cells leads to cellular transformation,characterized by the ability of cells to grow in soft agar and thegrowth of cells as dense foci lacking the contact inhibition exhibitedby non-transformed cells. Mutation and/or overexpression of certainoncogenes is frequently associated with human cancer. A particular groupof oncogenes is known as ras which have been identified in mammals,birds, insects, mollusks, plants, fungi and yeasts. The family ofmammalian ras oncogenes consists of three major members (“isoforms”):H-ras, K-ras and N-ras oncogenes. These ras oncogenes code for highlyrelated proteins generically known as p21^(ras). Once attached to plasmamembranes, the mutant or oncogenic forms of p21^(ras) will provide asignal for the transformation and uncontrolled growth of malignant tumorcells. To acquire this transforming potential, the precursor of thep21^(ras) oncoprotein must undergo an enzymatically catalyzedfarnesylation of the cysteine residue located in a carboxyl-terminaltetrapeptide. Therefore, inhibitors of the enzymes that catalyzes thismodification, i.e. farnesyl transferase, will prevent the membraneattachment of p21^(ras) and block the aberrant growth of ras-transformedtumors Hence, it is generally accepted in the art that farnesyltransferase inhibitors can be very useful as anticancer agents fortumors in which ras contributes to transformation.

The K-ras B isoform has been observed to be the dominant isoform whichis mutated in human cancers, particular in colon (50% incidence) andpancreatic (90% incidence) cancers. However, it was also found that rasprotein activation in the K-ras B isoform transformed cancers isresistant to inhibition of farnesyl transferase. The isoform confersresistance to farnesyl transferase inhibitors, but makes this isoformalso substrate for geranylgeranyl transferase I. Therefore, inhibitorsof geranylgeranyl transferase may inhibit the aberrant growth of K-rastransformed tumors which are resistant to farnesyl transferaseinhibitors.

Since mutated oncogenic forms of ras are frequently found in many humancancers, most notably in more than 50% of colon and pancreaticcarcinomas (Kohl et al., Science, vol 260, 1834-1837, 1993), it has beensuggested that farnesyl tranferase inhibitors can be very useful againstthese types of cancer.

In EP-0,371,564 there are described (1H-azol-1-ylmethyl) substitutedquinoline and quinolinone derivatives which suppress the plasmaelimination of retinoic acids. Some of these compounds also have theability to inhibit the formation of androgens from progestines and/orinhibit the action of the aromatase enzyme complex.

In WO 97/16443, WO 97/21701, WO 98/40383 and WO 98/49157, there aredescribed 2-quinolone derivatives which exhibit farnesyl transferaseinhibiting activity.

Unexpectedly, it has been found that the present novel 1,2-annelatedquinoline compounds, bearing a nitrogen- or carbon-linked imidazole,show farnesyl protein transferase and geranylgeranyl transferaseinhibiting activity.

The present invention concerns compounds of formula

or the pharmaceutically acceptable acid addition salts and thestereochemically isomeric forms thereof, wherein

-   ═X¹—X²—X³— is a trivalent radical of formula

═N—CR⁶═CR⁷— (x-1), ═CR⁶—CR⁷═CR⁸— (x-6), ═N—N═CR⁶— (x-2), ═CR⁶—N═CR⁷—(x-7), ═N—NH—C(═O)— (x-3), ═CR⁶—NH—C(═O)— (x-8), or ═N—N═N— (x-4),═CR⁶—N═N— (x-9); ═N—CR⁶═N— (x-5),

-   -   wherein each R⁶, R⁷ and R⁸ are independently hydrogen,        C₁₋₄alkyl, hydroxy, C₁₋₄alkyloxy, aryloxy, C₁₋₄alkyloxycarbonyl,        hydroxyC₁₋₄alkyl, C₁₋₄alkyloxyC₁₋₄alkyl, mono- or        di(C₁₋₄alkyl)aminoC₁₋₄alkyl, cyano, amino, thio, C₁₋₄alkylthio,        arylthio or aryl;

-   >Y¹—Y²— is a trivalent radical of formula    >CH—CHR⁹—  (y-1),    >C═N—  (y-2),    >CH—NR⁹—  (y-3),or    >C═CR⁹—  (y-4);    -   wherein each R⁹ independently is hydrogen, halo, halocarbonyl,        aminocarbonyl, hydroxyC₁₋₄alkyl, cyano, carboxyl, C₁₋₄alkyl,        C₁₋₄alkyloxy, C₁₋₄alkyloxyC₁₋₄alkyl, C₁₋₄alkyloxycarbonyl, mono-        or di(C₁₋₄alkyl)amino, mono- or di(C₁₋₄alkyl)aminoC₁₋₄alkyl,        aryl;

-   r and s are each independently 0, 1, 2, 3, 4 or 5;

-   t is 0, 1, 2 or 3;

-   each R¹ and R²are independently hydroxy, halo, cyano, C₁₋₆alkyl,    trihalomethyl, trihalomethoxy, C₂₋₆alkenyl, C₁₋₆alkyloxy,    hydroxyC₁₋₆alkyloxy, C₁₋₆alkylthio, C₁₋₆alkyloxyC₁₋₆alkyloxy,    C₁₋₆alkyloxycarbonyl, aminoC₁₋₆alkyloxy, mono- or    di(C₁₋₆alkyl)amino, mono- or di(C₁₋₆alkyl)aminoC₁₋₆alkyloxy, aryl,    arylC₁₋₆alkyl, aryloxy or arylC₁₋₆alkyloxy, hydroxycarbonyl,    C₁₋₆alkyloxycarbonyl, aminocarbonyl, aminoC₁₋₆alkyl, mono- or    di(C₁₋₆alkyl)aminocarbonyl, mono- or di(C₁₋₆alkyl)aminoC₁₋₆alkyl; or

-   two R¹ or R² substituents adjacent to one another on the phenyl ring    may independently form together a bivalent radical of formula    —O—CH₂—O—  (a-1),    —O—CH₂—CH₂—O—  (a-2),    —O—CH═CH—  (a-3),    —O—CH₂—CH₂—  (a-4),    —O—CH₂—CH₂—CH₂—  (a-5), or    —CH═CH—CH═CH—  (a-6);

-   R³ is hydrogen, halo, C₁₋₆alkyl, cyano, haloC₁₋₆alkyl,    hydroxyC₁₋₆alkyl, cyanoC₁₋₆alkyl, aminoC₁₋₆alkyl,    C₁₋₆alkyloxyC₁₋₆alkyl, C₁₋₆alkylthioC₁₋₆alkyl,    aminocarbonylC₁₋₆alkyl, hydroxycarbonyl, hydroxycarbonylC₁₋₆alkyl,    C₁₋₆alkyloxycarbonylC₁₋₆alkyl, C₁₋₆alkylcarbonylC₁₋₆alkyl,    C₁₋₆alkyloxycarbonyl, aryl, arylC₁₋₆alkyloxyC₁₋₆alkyl, mono- or    di(C₁₋₆alkyl)aminoC₁₋₆alkyl;    or a radical of formula    —O—R¹⁰  (b-1),    —S—R¹⁰  (b-2),    —NR¹¹R¹²  (b-3),    wherein    -   R¹⁰ is hydrogen, C₁₋₆alkyl, C₁₋₆alkylcarbonyl, aryl,        arylC₁₋₆alkyl, C₁₋₆alkyloxycarbonylC₁₋₆alkyl, or a radical of        formula -Alk-OR¹³ or -Alk-NR¹⁴R¹⁵;    -   R¹¹ is hydrogen, C₁₋₆alkyl, aryl or arylC₁₋₆alkyl;    -   R¹² is hydrogen, C₁₋₆alkyl, aryl, hydroxy, amino, C₁₋₆alkyloxy,        C₁₋₆alkylcarbonylC₁₋₆alkyl, arylC₁₋₆alkyl,        C₁₋₆alkylcarbonylamino, mono- or di(C₁₋₆alkyl)amino,        C₁₋₆alkylcarbonyl, aminocarbonyl, arylcarbonyl,        haloC₁₋₆alkylcarbonyl, arylC₁₋₆alkylcarbonyl,        C₁₋₆alkyloxycarbonyl, C₁₋₆alkyloxyC₁₋₆alkylcarbonyl, mono- or        di(C₁₋₆alkyl)aminocarbonyl wherein the alkyl moiety may        optionally be substituted by one or more substituents        independently selected from aryl or C₁₋₃alkyloxycarbonyl,        aminocarbonylcarbonyl, mono- or        di(C₁₋₆alkyl)aminoC₁₋₆alkylcarbonyl, or a radical or formula        -Alk-OR¹³ or -Alk-NR¹⁴R¹⁵;        wherein Alk is C₁₋₆alkanediyl;    -   R¹³ is hydrogen, C₁₋₆alkyl, C₁₋₆alkylcarbonyl, hydroxyC₁₋₆alkyl,        aryl or arylC₁₋₆alkyl;    -   R¹⁴ is hydrogen, C₁₋₆alkyl, aryl or arylC₁₋₆alkyl;    -   R¹⁵ is hydrogen, C₁₋₆alkyl, C₁₋₆alkylcarbonyl, aryl or        arylC₁₋₆alkyl;

-   R⁴ is a radical of formula    wherein    -   R¹⁶ is hydrogen, halo, aryl, C₁₋₆alkyl, hydroxyC₁₋₆alkyl,        C₁₋₆alkyloxyC₁₋₆alkyl, C₁₋₆alkyloxy, C₁₋₆alkylthio, amino, mono        or di(C₁₋₄alkyl)amino, hydroxycarbonyl, C₁₋₆alkyloxycarbonyl,        C₁₋₆alkylthioC₁₋₆alkyl, C₁₋₆alkylS(O)C₁₋₆alkyl or        C₁₋₆alkylS(O)₂C₁₋₆alkyl;    -   R¹⁶ may also be bound to one of the nitrogen atoms in the        imidazole ring of formula (c-1) or (c-2), in which case the        meaning of R¹⁶ when bound to the nitrogen is limited to        hydrogen, aryl, C₁₋₆alkyl, hydroxyC₁₋₆alkyl,        C₁₋₆alkyloxyC₁₋₆alkyl, C₁₋₆alkyloxycarbonyl,        C₁₋₆alkylS(O)C₁₋₆alkyl or C₁₋₆alkylS(O)₂C₁₋₆alkyl;    -   R¹⁷ is hydrogen, C₁₋₆alkyl, C₁₋₆alkyloxyC₁₋₆alkyl,        arylC₁₋₆alkyl, trifluoromethyl or di(C₁₋₄alkyl)aminosulfonyl;        R⁵ is C₁₋₆alkyl, C₁₋₆alkyloxy or halo;        aryl is phenyl, naphthalenyl or phenyl substituted with 1 or        more substituents each independently selected from halo,        C₁₋₆alkyl, C₁₋₆alkyloxy or trifluoromethyl

A special group of compounds contains those compounds of formula (I)wherein

-   each R¹ and R² are independently hydroxy, halo, cyano, C₁₋₆alkyl,    trihalomethyl, trihalomethoxy, C₂₋₆alkenyl, C₁₋₆alkyloxy,    hydroxyC₁₋₆alkyloxy, C₁₋₆alkylthio, C₁₋₆alkyloxyC₁₋₆alkyloxy,    C₁₋₆alkyloxycarbonyl, aminoC₁₋₆alkyloxy, mono- or    di(C₁₋₆alkyl)amino, mono- or di(C₁₋₆alkyl)aminoC₁₋₆alkyloxy, aryl,    arylC₁₋₆alkyl, aryloxy or arylC₁₋₆alkyloxy, hydroxycarbonyl,    C₁₋₆alkyloxycarbonyl; or-   two R¹ or R² substituents adjacent to one another on the phenyl ring    may independently form together a bivalent radical of formula    —O—CH₂—O—  (a-1),    —O—CH₂—CH₂—O—  (a-2),    —O—CH═CH—  (a-3),    —O—CH₂—CH₂—  (a-4),    —O—CH₂—CH₂—CH₂—  (a-5), or    —CH═CH—CH═CH—  (a-6);-   R¹⁶ is hydrogen, halo, aryl, C₁₋₆alkyl, hydroxyC₁₋₆alkyl,    C₁₋₆alkyloxyC₁₋₆alkyl, C₁₋₆alkyloxy, C₁₋₆alkylthio, amino, mono- or    di(C₁₋₄alkyl)amino, hydroxycarbonyl, C₁₋₆alkyloxycarbonyl,    C₁₋₆alkylthioC₁₋₆alkyl, C₁₋₆alkylS(O)C₁₋₆alkyl or    C₁₋₆alkylS(O)₂C₁₋₆alkyl;-   R¹⁶ may also be bound to one of the nitrogen atoms in the imidazole    ring of formula (c-1), in which case the meaning of R¹⁶ when bound    to the nitrogen is limited to hydrogen, aryl, C₁₋₆alkyl,    hydroxyC₁₋₆alkyl, C₁₋₆alkyloxyC₁₋₆alkyl, C₁₋₆alkyloxycarbonyl,    C₁₋₆alkylS(O)C₁₋₆alkyl or C₁₋₆alkylS(O)₂C₁₋₆alkyl;-   R¹⁷ is hydrogen, C₁₋₆alkyl, trifluoromethyl or    di(C₁₋₄alkyl)aminosulfonyl.

As used in the foregoing definitions and hereinafter, halo is generic tofluoro, chloro, bromo and iodo; C₁₋₄alkyl defines straight and branchedchain saturated hydrocarbon radicals having from 1 to 4 carbon atomssuch as, e.g. methyl, ethyl, propyl, butyl, 1-methylethyl,2-methylpropyl and the like; C₁₋₆alkyl includes C₁₋₄alkyl and the higherhomologues thereof having 5 to 6 carbon atoms such as, for example,pentyl, 2-methyl-butyl, hexyl, 2-methylpentyl and the like;C₁₋₆alkanediyl defines bivalent straight and branched chained saturatedhydrocarbon radicals having from 1 to 6 carbon atoms, such as, forexample, methylene, 1,2-ethanediyl, 1,3-propanediyl, 1,4-butanediyl,1,5-pentanediyl, 1,6-hexanediyl and the branched isomers thereof;C₂₋₆alkenyl defines straight and branched chain hydrocarbon radicalscontaining one double bond and having from 2 to 6 carbon atoms such as,for example, ethenyl, 2-propenyl, 3-butenyl, 2-pentenyl, 3-pentenyl,3-methyl-2-butenyl, and the like. The term “S(O)” refers to a sulfoxideand “S(O)₂” to a sulfon.

The pharmaceutically acceptable acid addition salts as mentionedhereinabove are meant to comprise the therapeutically active non-toxicacid addition salt forms which the compounds of formula (I) are able toform. The compounds of formula (I) which have basic properties can beconverted in their pharmaceutically acceptable acid addition salts bytreating said base form with an appropriate acid. Appropriate acidscomprise, for example, inorganic acids such as hydrohalic acids, e.g.hydrochloric or hydrobromic acid; sulfuric; nitric; phosphoric and thelike acids; or organic acids such as, for example, acetic, propanoic,hydroxyacetic, lactic, pyruvic, oxalic, malonic, succinic (i.e.butanedioic acid), maleic, fumaric, malic, tartaric, citric,methanesulfonic, ethanesulfonic, benzenesulfonic, p-toluenesulfonic,cyclamic, salicylic, p-amino-salicylic, pamoic and the like acids.

The term acid addition salts also comprises the hydrates and the solventaddition forms which the compounds of formula (I) are able to form.Examples of such forms are e.g. hydrates, alcoholates and the like.

The term stereochemically isomeric forms of compounds of formula (I), asused hereinbefore, defines all possible compounds made up of the sameatoms bonded by the same sequence of bonds but having differentthree-dimensional structures which are not interchangeable, which thecompounds of formula (I) may possess. Unless otherwise mentioned orindicated, the chemical designation of a compound encompasses themixture of all possible stereochemically isomeric forms which saidcompound may possess. Said mixture may contain all diastereomers and/orenantiomers of the basic molecular structure of said compound. Allstereochemically isomeric forms of the compounds of formula (I) both inpure form or in admixture with each other are intended to be embracedwithin the scope of the present invention.

Some of the compounds of formula (I) may also exist in their tautomericforms. Such forms although not explicitly indicated in the above formulaare intended to be included within the scope of the present invention.

Whenever used hereinafter, the term “compounds of formula (I)” is meantto include also the pharmaceutically acceptable acid addition salts andall stereoisomeric forms.

A group of interesting compounds consists of those compounds of formula(I) wherein one or more of the following restrictions apply:

-   -   ═X¹—X²—X³ is a trivalent radical of formula (x-1), (x-2), (x-3),        (x-4) or (x-9) wherein each R⁶ independently is hydrogen,        C₁₋₄alkyl, C₁₋₄alkyloxycarbonyl, amino or aryl and R⁷ is        hydrogen;    -   >Y¹—Y²— is a trivalent radical of formula (y-1), (y-2), (y-3),        or (y-4) wherein each R⁹ independently is hydrogen, halo,        carboxyl, C₁₋₄alkyl or C₁₋₄alkyloxycarbonyl;    -   r is 0, 1 or 2;    -   s is 0 or 1;    -   t is 0;    -   R¹ is halo, C₁₋₆alkyl or two R¹ substituents ortho to one        another on the phenyl ring may independently form together a        bivalent radical of formula (a-1);    -   R² is halo;    -   R³ is halo or a radical of formula (b-1) or (b-3) wherein        -   R¹⁰ is hydrogen or a radical of formula -Alk-OR¹³.        -   R¹¹ is hydrogen;        -   R¹² is hydrogen, C₁₋₆alkyl, C₁₋₆alkylcarbonyl, hydroxy,            C₁₋₆alkyloxy or mono- or            di(C₁₋₆alkyl)aminoC₁₋₆alkylcarbonyl;        -   Alk is C₁₋₆alkanediyl and R¹³ is hydrogen;    -   R⁴ is a radical of formula (c-1) or (c-2) wherein        -   R¹⁶ is hydrogen, halo or mono- or di(C₁₋₄alkyl)amino;        -   R¹⁷ is hydrogen or C₁₋₆alkyl;    -   aryl is phenyl.

A particular group of compounds consists of those compounds of formula(I) wherein ═X¹—X²—X³ is a trivalent radical of formula (x-1), (x-2),(x-3) or (x-9), >Y1-Y2 is a trivalent radical of formula (y-2), (y-3) or(y-4), r is 0 or 1, s is 1, t is 0, R¹ is halo, C₍₁₋₄₎alkyl or forms abivalent radical of formula (a-1), R² is halo or C₁₋₄alkyl, R³ ishydrogen or a radical of formula (b-1) or (b-3), R⁴ is a radical offormula (c-1) or (c-2), R⁶ is hydrogen, C₁₋₄alkyl or phenyl, R⁷ ishydrogen, R⁹ is hydrogen or C₁₋₄alkyl, R¹⁰ is hydrogen or -Alk-OR¹³, R¹¹is hydrogen and R¹² is hydrogen or C₁₋₆alkylcarbonyl and R¹³ ishydrogen;

Preferred compounds are those compounds of formula (I) wherein ═X¹—X²—X³is a trivalent radical of formula (x-1), >Y1-Y2 is a trivalent radicalof formula (y-4), r is 0 or 1, s is 1, t is 0, R¹ is halo, preferablychloro and most preferably 3-chloro, R² is halo, preferably 4-chloro or4-fluoro, R³ is hydrogen or a radical of formula (b-1) or (b-3), R⁴ is aradical of formula (c-1) or (c-2), R⁶ is hydrogen, R⁷ is hydrogen, R⁹ ishydrogen, R¹⁰ is hydrogen, R¹¹ is hydrogen and R¹² is hydrogen;

Other preferred compounds are those compounds of formula (I) wherein═X¹—X²—X³ is a trivalent radical of formula (x-2) or (x-3), >Y1-Y2 is atrivalent radical of formula (y-2), (y-3) or (y-4), r and s are 1, t is0, R¹ is halo, preferably chloro, and most preferably 3-chloro or R¹ isC₁₋₄alkyl, preferably 3-methyl, R² is halo, preferably chloro, and mostpreferably 4-chloro, R³ is a radical of formula (b-1) or (b-3), R⁴ is aradical of formula (c-2), R⁶ is C₁₋₄alkyl, R⁹ is hydrogen, R¹⁰ and R¹¹are hydrogen and R¹² is hydrogen or hydroxy;

The most preferred compounds of formula (I) are7-[(4-fluorophenyl)(1H-imidazol-1-yl)methyl]-5-phenylimidazo[1,2-a]quinoline;α-(4-chlorophenyl)-α-(1-methyl-1H-imidazol-5-yl)-5-phenylimidazo[1,2-a]quinoline-7-methanol;5-(3-chlorophenyl)-α-(4-chlorophenyl)-α-(1-methyl-1H-imidazol-5-yl)-imidazo[1,2-a]quinoline-7-methanol;5-(3-chlorophenyl)-α-(4-chlorophenyl)-α-(1-methyl-1H-imidazol-5-yl)imidazo[1,2-a]quinoline-7-methanamine;5-(3-chlorophenyl)-α-(4-chlorophenyl)-α-(1-methyl-1H-imidazol-5-yl)tetrazolo[1,5-a]quinoline-7-methanamine;5-(3-chlorophenyl)-α-(4-chlorophenyl)-1-methyl-α-(1-methyl-1H-imidazol-5-yl)-1,2,4-triazolo[4,3-a]quinoline-7-methanol;5-(3-chlorophenyl)-α-(4-chlorophenyl)-α(1-methyl-1H-imidazol-5-yl)tetrazolo[1,5-a]quinoline-7-methanamine;5-(3-chlorophenyl)-α-(4-chlorophenyl)-α-(1-methyl-1H-imidazol-5-yl)tetrazolo[1,5-a]quinazoline-7-methanol;5-(3-chlorophenyl)-α-(4-chlorophenyl)-4,5-dihydro-α-(1-methyl-1H-imidazol-5-yl)tetrazolo[1,5-a]quinazoline-7-methanol;5-(3-chlorophenyl)-α-(4-chlorophenyl)-α-(1-methyl-1H-imidazol-5-yl)tetrazolo[1,5-a]quinazoline-7-methanamine;5-(3-chlorophenyl)-α-(4-chlorophenyl)-N-hydroxy-α-(1-methyl-1H-imidazol-5-yl)tetrahydro[1,5-a]quinoline-7-methanamine;α-(4-chlorophenyl)-α-(1-methyl-1H-imidazol-5-yl)-5-(3-methylphenyl)tetrazolo[1,5-a]quinoline-7-methanamine;the pharmaceutically acceptable acid addition salts and thestereochemically isomeric forms thereof.

The compounds of formula (I) wherein ═X¹—X²—X³ is a trivalent radical offormula (x-1) and R⁶ and R⁷ are hydrogen, represented by compounds offormula (I-1), can generally be prepared by reacting an intermediate offormula (II) with a reagent of formula (III) or a functional derivativethereof, wherein W¹ is an appropriate leaving group such as chloro,followed by an intramolecular cyclization which can be performed in areaction-inert solvent such as xylene and in the presence of a suitableacid, for example acetic acid. The reaction may conveniently be carriedout at elevated temperatures ranging from 80° C. to reflux temperature.

Alternatively, compounds of formula (I) wherein ═X¹—X²—X³ is a trivalentradical of formula (x-1), >Y¹—Y² is a trivalent radical of formula(y-4), R⁹ is hydrogen and R⁶ and/or R⁷ are not hydrogen, represented byformula (I-1-a) can be prepared by reacting a compound of formula (IV)with a reagent of formula (V) followed by an intramolecular cyclizationwhich can be performed in a reaction-inert solvent such as ethanol. Thereaction may conveniently be carried out at temperatures ranging fromroom temperature to 80° C.

The compounds of formula (I) wherein ═X¹—X²—X³ is a trivalent radical offormula (x-2), represented by compounds of formula (I-2), can generallybe prepared by reacting a compound of formula (II) with an intermediateof formula (VI). Said reaction can be performed in an appropriatesolvent such as 1-butanol at elevated temperatures ranging from 80° C.to reflux temperature.

Alternatively, compounds of formula (I-2) can be prepared by reacting acompound of formula (VIII) with an intermediate of formula (VII). Saidreaction can be performed in an appropriate solvent such as n-butanol ata temperature ranging between room temperature and reflux temperature.The intermediates of formula (VII) can be prepared by reacting anintermediate of formula (II) with N₂H₄. Said reaction can be performedin a reaction-inert solvent such as dioxane. The reaction mayconveniently be carried out at a temperature ranging between roomtemperature and 100° C.

Compounds of formula (I-2) wherein R⁶ is an amine, represented bycompounds of formula (I-2-a) can be prepared by reacting an intermediateof formula (VII) with BrCN in a reaction-inert solvent such as methanol.The reaction may conveniently be carried out at a temperature rangingbetween 0° C. and 100° C.

The compounds of formula (I) wherein ═X¹—X²—X³ is a trivalent radical offormula (x-3), represented by compounds of formula (I-3), can generallybe prepared by reacting an intermediate of formula (VII) with a compoundof formula (IX) in a reaction-inert solvent such as tetrahydrofuran. Thereaction may conveniently be carried out at a temperature rangingbetween 0° C. and 50° C.

Alternatively, the compounds of formula (I-3) can be prepared byreacting a compound of formula (X) with an intermediate of formula (II).Said reaction can be performed in an appropriate solvent such as1-butanol at an elevated temperature ranging from 80° C. to refluxtemperature.

The compounds of formula (I) wherein ═X¹—X²—X³ is a trivalent radical offormula (x-4), represented by compounds of formula (I-4), can generallybe prepared by reacting an intermediate of formula (II) with NaN₃ in areaction-inert solvent such as N,N-dimethylformamide. The reaction mayconveniently be carried out at an elevated temperature ranging between60° C. and 150° C.

The compounds of formula (I-4) can also be prepared by reacting anintermediate of formula (XVIII) with NaNO₂ in an acidic aqueous mediumsuch as, for example HCl in water.

The compounds of formula (I) wherein ═X¹—X²—X³ is a trivalent radical offormula (x-9), >Y¹—Y² is a trivalent radical of formula (y-4) and R⁹ ishydrogen, represented by compounds of formula (I-5), can generally beprepared by reacting an intermediate of formula (XI) with a compound offormula (XII) in a reaction-inert solvent such as methanol. Convenientreaction temperatures range between room temperature and 80° C. Theintermediates of formula (XI) can be prepared by reacting anintermediate of formula (XIII) with SeO₂ in a reaction-inert solventsuch as dioxane. The reaction may conveniently be carried out at anelevated temperature ranging between room temperature and refluxtemperature. Intermediates of formula (XIII) can generally be preparedby reacting an intermediate of formula (XIV) with 2-propanone in an acidsolution such as a mixture of acetic acid and H₂SO₄. The reaction mayconveniently be carried out at an elevated temperature ranging betweenroom temperature and reflux temperature.

Compounds of formula (I-6) defined as compounds of formula (I) wherein>Y¹—Y² is a trivalent radical of formula (y-2) or (y-4) can be convertedto the corresponding compounds of formula (I-7) wherein >Y¹—Y² is atrivalent radical of formula (y-3) or (y-1) and R⁹ is hydrogen, usingart-known reduction procedures such as treatment with NaBH₄ or LiAlH₄ ina suitable solvent such as methanol or tetrahydrofuran.

Conversely, compounds of formula (I-7) can be converted to thecorresponding compounds of formula (I-6) by art-known oxidationprocedures such as oxidation with MnO₂ in a reaction-inert solvent suchas dichloromethane.

Also, compounds of formula (I-7) can be converted to compounds offormula (I-7-a) wherein >Y¹—Y²is a trivalent radical of formula (y-3) or(y-1) and R⁹ is other than hydrogen, by reacting these compounds offormula (I-7) with a reagent of formula R⁹—W², wherein W² is anappropriate leaving group such as iodo, in a reaction-inert solvent suchas dimethylformamide and in the presence of NaH. The reaction mayconveniently be carried out at a temperature ranging between 0° C. androom temperature.

The compounds of formula (I) wherein R³ is a radical of formula (c-2)and R⁴ is V20 hydroxy, represented by compounds of formula (I-8) can beconverted to compounds of formula (I-8-a) wherein R⁴ is hydrogen, bysubmitting the compounds of formula (I-8) to appropriate reducingconditions such as stirring in acetic acid in the presence of formamide.

Further, compounds of formula (I-8) can be converted to compounds offormula (I-8-b) wherein R⁴ is halo, by reacting the compounds of formula(I-8) with a suitable halogenating agent such as thionyl chloride orphosphorus tribromide. Successively, the compounds of formula (I-8-b)can be treated with a reagent of formula H—NR¹¹R¹² in a reaction-inertsolvent, thereby yielding compounds of formula (I-8-c).

The intermediates of formula (II) can be prepared by reacting anintermediate of formula (XV) with a suitable halogenating reagent suchas POCl₃.

The intermediates of formula (XV) wherein >Y¹—Y² is of formula (y-1) or(y-4) and R⁴ is of formula (c-1), can be prepared as described in WO97/16443 from page 6 line 16 to page 16 line 3.

The intermediates of formula (XV) wherein >Y¹—Y² is of formula (y-1) or(y-4) and R⁴ is of formula (c-2), can be prepared as described in WO97/21701 from page 7 line 28 to page 16 line 3.

The intermediates of formula (XV) wherein >Y¹—Y² is of formula (y-2) or(y-3) and R⁴ is of formula (c-1) or (c-2), can be prepared as describedin WO 98/49157 from page 6 line 27 to page 13 line 14.

Alternatively, intermediates of formula (II) wherein W¹ is chloro and R³is hydroxy, represented by intermediates of formula (II-a) can beprepared by reacting an intermediate of formula (XVI), wherein W³ is asuitable leaving group such as Br, with an intermediate ketone offormula (XVII). This reaction is performed by converting theintermediate of formula (XVI) into an organometallic compound, bystirring it with a strong base such as butyl lithium and subsequentlyadding the intermediate ketone of formula (XVII). The hydroxy derivativecan subsequently be converted into other intermediates wherein R⁴ hasanother definition by performing art-known functional grouptransformations.

Intermediates of formula (IV) can be prepared by reacting anintermediate of formula (XIV) with CH₃CN in the presence of NaH and asuitable base such as pyridine. The reaction may conveniently be carriedout at an elevated temperature ranging between 50° C. and 100° C.

Intermediates of formula (XIV) can be prepared according to methods asdescribed in WO 97/16443 and WO 97/21701.

The compounds of formula (I) and some of the intermediates have at leastone stereogenic center in their structure. This stereogenic center maybe present in a R or a S configuration.

The compounds of formula (I) as prepared in the hereinabove describedprocesses are generally racemic mixtures of enantiomers which can beseparated from one another following art-known resolution procedures.The racemic compounds of formula (I) may be converted into thecorresponding diastereomeric salt forms by reaction with a suitablechiral acid. Said diastereomeric salt forms are subsequently separated,for example, by selective or fractional crystallization and theenantiomers are liberated therefrom by alkali. An alternative manner ofseparating the enantiomeric forms of the compounds of formula (I)involves liquid chromatography using a chiral stationary phase. Saidpure stereochemically isomeric forms may also be derived from thecorresponding pure stereochemically isomeric forms of the appropriatestarting materials, provided that the reaction occursstereospecifically. Preferably if a specific stereoisomer is desired,said compound will be synthesized by stereospecific methods ofpreparation. These methods will advantageously employ enantiomericallypure starting materials.

The compounds of formula (I), the pharmaceutically acceptable acidaddition salts and stereoisomeric forms thereof have valuablepharmacological properties in that they surprisingly have both farnesylprotein transferase (FPTase) and geranylgeranyl transferase (GGTase)inhibitory effects.

Furthermore, the compounds of formula (I), in particular those compoundsof formula (I) wherein ═X¹—X²—X³ is a trivalent radical of formula(x-4), display potent GGTase inhibition.

Other compounds of formula (I) are found to be particularly usefull forthe inhibition of FPTase activity.

This invention provides a method for inhibiting the abnormal growth ofcells, including transformed cells, by administering an effective amountof a compound of the invention. Abnormal growth of cells refers to cellgrowth independent of normal regulatory mechanisms (e.g. loss of contactinhibition). This includes the abnormal growth of: (1) tumor cells(tumors) expressing an activated ras oncogene; (2) tumor cells in whichthe ras protein is activated as a result of oncogenic mutation ofanother gene; (3) benign and malignant cells of other proliferativediseases in which aberrant ras activation occurs. Furthermore, it hasbeen suggested in literature that ras oncogenes not only contribute tothe growth of tumors in vivo by a direct effect on tumor cell growth butalso indirectly, i.e. by facilitating tumor-induced angiogenesis (Rak.J. et al, Cancer Research, 55, 4575-4580, 1995). Hence,pharmacologically targeting mutant ras oncogenes could conceivablysuppress solid tumor growth in vivo, in part, by inhibitingtumor-induced angiogenesis.

This invention also provides a method for inhibiting tumor growth byadministering an effective amount of a compound of the presentinvention, to a subject, e.g. a mammal (and more particularly a human)in need of such treatment. In particular, this invention provides amethod for inhibiting the growth of tumors expressing an activated rasoncogene by the administration of an effective amount of the compoundsof the present invention. Examples of tumors which may be inhibited, butare not limited to, lung cancer (e.g. adenocarcinoma), pancreaticcancers (e.g. pancreatic carcinoma such as, for example exocrinepancreatic carcinoma), colon cancers (e.g. colorectal carcinomas, suchas, for example, colon adenocarcinoma and colon adenoma), hematopoietictumors of lymphoid lineage (e.g. acute lymphocytic leukemia, B-celllymphoma, Burkitt's lymphoma), myeloid leukemias (for example, acutemyelogenous leukemia (AML)), thyroid follicular cancer, myelodysplasticsyndrome (MDS), tumors of mesenchymal origin (e.g. fibrosarcomas andrhabdomyosarcomas), melanomas, teratocarcinomas, neuroblastomas,gliomas, benign tumor of the skin (e.g. keratoacanthomas), breastcarcinoma, kidney carcinoma, ovary carcinoma, bladder carcinoma andepidermal carcinoma.

This invention may also provide a method for inhibiting proliferativediseases, both benign and malignant, wherein ras proteins are aberrantlyactivated as a result of oncogenic mutation in genes. With saidinhibition being accomplished by the administration of an effectiveamount of the compounds described herein, to a subject in need of such atreatment. For example, the benign proliferative disorderneuro-fibromatosis, or tumors in which ras is activated due to mutationor overexpression of tyrosine kinase oncogenes, may be inhibited by thecompounds of this invention.

The compounds of present invention are particularly useful for thetreatment of proliferative diseases, both benign and malignant, whereinthe K-ras B isoform is activated as a result of oncogenic mutation.

Hence, the present invention discloses the compounds of formula (I) foruse as a medicine as well as the use of these compounds of formula (I)for the manufacture of a medicament for treating one or more of theabove mentioned conditions.

In view of their useful pharmacological properties, the subjectcompounds may be formulated into various pharmaceutical forms foradministration purposes.

To prepare the pharmaceutical compositions of this invention, aneffective amount of a particular compound, in base or acid addition saltform, as the active ingredient is combined in intimate admixture with apharmaceutically acceptable carrier, which carrier may take a widevariety of forms depending on the form of preparation desired foradministration. These pharmaceutical compositions are desirably inunitary dosage form suitable, preferably, for administration orally,rectally, percutaneously, or by parenteral injection. For example, inpreparing the compositions in oral dosage form, any of the usualpharmaceutical media may be employed, such as, for example, water,glycols, oils, alcohols and the like in the case of oral liquidpreparations such as suspensions, syrups, elixirs and solutions; orsolid carriers such as starches, sugars, kaolin, lubricants, binders,disintegrating agents and the like in the case of powders, pills,capsules and tablets. Because of their ease in administration, tabletsand capsules represent the most advantageous oral dosage unit form, inwhich case solid pharmaceutical carriers are obviously employed. Forparenteral compositions, the carrier will usually comprise sterilewater, at least in large part, though other ingredients, to aidsolubility for example, may be included. Injectable solutions, forexample, may be prepared in which the carrier comprises saline solution,glucose solution or a mixture of saline and glucose solution. Injectablesuspensions may also be prepared in which case appropriate liquidcarriers, suspending agents and the like may be employed. In thecompositions suitable for percutaneous administration, the carrieroptionally comprises a penetration enhancing agent and/or a suitablewetting agent, optionally combined with suitable additives of any naturein minor proportions, which additives do not cause a significantdeleterious effect to the skin. Said additives may facilitate theadministration to the skin and/or may be helpful for preparing thedesired compositions. These compositions may be administered in variousways, e.g., as a transdermal patch, as a spot-on, as an ointment. It isespecially advantageous to formulate the aforementioned pharmaceuticalcompositions in dosage unit form for ease of administration anduniformity of dosage. Dosage unit form as used in the specification andclaims herein refers to physically discrete units suitable as unitarydosages, each unit containing a predetermined quantity of activeingredient calculated to produce the desired therapeutic effect inassociation with the required pharmaceutical carrier. Examples of suchdosage unit forms are tablets (including scored or coated tablets),capsules, pills, powder packets, wafers, injectable solutions orsuspensions, teaspoonfuls, tablespoonfuls and the like, and segregatedmultiples thereof.

Those skilled in the art could easily determine the effective amountfrom the test results presented hereinafter. In general it iscontemplated that an effective amount would be from 0.01 mg/kg to 100mg/kg body weight, and in particular from 0.05 mg/kg to 10 mg/kg bodyweight. It may be appropriate to administer the required dose as two,three, four or more sub-doses at appropriate intervals throughout theday. Said sub-doses may be formulated as unit dosage forms, for example,containing 0.5 to 500 mg, and in particular 1 mg to 200 mg of activeingredient per unit dosage form.

The following examples are provided for purposes of illustration.

Experimental Part

Hereinafter “THF” means tetrahydrofuran, “DIE” means diisopropylether,“DME” means 1,2-dimethoxyethane and “EtOAc” means ethylacetate.

A. Preparation of the Intermediates

EXAMPLE A1

a) A mixture of(±)-6-[(4-fluorophenyl)(1H-imidazol-1-yl)methyl]4-phenyl-2(1H)-quinolinone(0.0253 mol) in phosphoryl chloride (30 ml) was refluxed for 1 hour. Themixture was evaporated till dryness and the product was used withoutfurther purification, yielding 10.4 g (99%) of(±)-2-chloro-6[(4-fluorophenyl)(1H-imidazol-1-yl)methyl]phenyl-quinoline(interm. 1).

b) A mixture of intermediate (1) (0.0251 mol) in 2,2-dimethoxyethylamine(20 ml) was stirred at 120° C. for 12 hours. The mixture was poured intoice water and extracted with CH₂Cl₂. The organic layer was dried (MgSO₄)and evaporated till dryness. The oily residue (21 g) was purified bycolumn chromatography over silica gel. The pure fractions were collectedand evaporated, yielding 10 g (83%) of(±)-N-(2,2-dimethoxyethyl)-6-[(4-fluorophenyl)(1H-imidazol-1-yl)methyl]-4-phenyl-2-quinolinamine(interm. 2).

EXAMPLE A2

a) Preparation of

Sodium hydride (0.0384 mol) was added portionwise to a mixture of(±)-[2-amino-5-[(4-chlorophenyl)hydroxy(1-methyl-1H-imidazol-5-yl)methylphenyl](3-chloro-phenyl)methanone(0.00961 mol) and acetonitrile (0.058 mol) in pyridine (30 ml). Themixture was stirred at 90° C. for 6 hours and then cooled. H₂O wasadded. The solvent was evaporated. The residue was taken up in CH₂Cl₂.The organic solution was washed with H₂O, dried (MgSO₄), filtered andthe solvent was evaporated. The residue (6.1 g) was purified by columnchromatography over silica gel. The pure fractions were collected andthe solvent was evaporated, yielding 2.9 g (63%) of intermediate 3.b) Preparation of

Ethyl bromopyruvate (0.0023 mol) was added to a mixture of intermediate(3) (0.0019 mol) in DME (5 ml). The mixture was stirred at roomtemperature for 19 hours. A gum was filtered off, washed with diethylether and used without further purification, yielding intermediate (4).

EXAMPLE A3

A mixture of(±)-6-[(4-chlorophenyl)-1H-imidazol-1-ylmethyl]-4phenyl-2(1H)-quinolinone(0.022 mol) in phosphoryl chloride (100 ml) was stirred and refluxed for2 hours. The mixture was evaporated in vacuo, the residue was taken upin CH₂Cl₂ and basified with K₂CO₃ (10%). The organic layer was dried(MgSO₄), filtered off and evaporated. The product was used withoutfurther purification, yielding 8 g (85%) of(±)-2-chloro-6-[(4-chlorophenyl)-1H-imidazol-1-ylmethyl]-4-phenylquinoline(interm. 5).

EXAMPLE A4

A mixture of intermediate (6) (0.0242 mol) in hydrazine hydrate (120 ml)and dioxane (240 ml) was stirred at 70° C. overnight and then brought toroom temperature. H₂O was added and the mixture was extracted withCH₂Cl₂. The organic layer was separated, washed with a saturated NaClsolution, dried (MgSO₄), filtered and the solvent was evaporated,yielding 11.8 g of intermediate 7.

EXAMPLE A5

A solution of butyllithium in hexane (1.6 M) (74.4 ml) was addeddropwise at −70° C. under N₂ flow to a mixture of 1-methylimidazole(0.119 mol) in THF (200 ml). The mixture was stirred at −70° C. for 30minutes. Chlorotriethylsilane (0.119 mol) was added. The mixture wasbrought slowly to 10° C. and cooled again to −70° C. A solution ofbutyllithium in hexane (1.6 M) (74.4 ml) was added dropwise. The mixturewas stirred at −70° C. for 1 hour, brought to −15° C. and cooled againto −70° C. A mixture of intermediate (8) (0.052 mol) in THF (200 ml) wasadded dropwise. The mixture was stirred at −70° C. for 30 min,hydrolized, extracted with EtOAc and decanted. The organic layer wasdried (MgSO₄), filtered and the solvent was evaporated. The residue waspurified by column chromatography over silica gel. The pure fractionswere collected and the solvent was evaporated, yielding 12 g (46.5%) ofintermediate (9).

EXAMPLE A6

a) Preparation of

A mixture of(±)-(2-amino-5-[(4-chlorophenyl)hydroxy(1-methyl-1H-imidazol-5-yl)methyl]phenyl](3-chlorophenyl)methanone(0.0415 mol) and 2-propanone (0.124 mol) in sulfuric acid (0.6 ml) andacetic acid (55 ml) was stirred and refluxed overnight, brought to roomtemperature, poured out on ice, basified with NH₄OH and extracted withCH₂Cl₂. The organic layer was separated, dried (MgSO₄), filtered and thesolvent was evaporated. The residue (30 g) was purified by columnchromatography over silica gel. The pure fractions were collected andthe solvent was evaporated, yielding 12 g (60%) of product. Part of thisfraction (2 g) was crystallized from CH₃CN. The precipitate was filteredoff and dried, yielding 1.25 g (37.5%) of intermediate (10).b) Preparation of

A mixture of intermediate (10) (0.0116 mol) and selenium dioxide (0.0116mol) in dioxane (55 ml) and water (5.5 ml) was stirred and refluxed for3 hours. The mixture was cooled, filtered over celite, washed withCH₂Cl₂, dried (MgSO₄), filtered and the solvent was evaporated, yielding5.66 g of intermediate (11).

EXAMPLE A7

Butyllithium in hexane (1.6 M) (5.3 ml) was added dropwise at −70° C. toa mixture of intermediate (12) (0.0071 mol) in tetrahydrofuran (25 ml).The mixture was stirred at −70° C. for 30 minutes. A solution ofintermediate (13) (0.0078 mol) in THF (10 ml) was added dropwise. Themixture was stirred for 1 hour, hydrolized and extracted with EtOAc. Theorganic layer was separated, dried (MgSO₄), filtered and the solvent wasevaporated till dryness. The residue (3.9 g) was purified by columnchromatography over silica gel. Two pure fractions were collected andtheir solvents were evaporated, yielding 1.3 g (65%; starting material(intermediate 13) and 0.71 g (19%) of intermediate (14).

EXAMPLE A8

Preparation of

A mixture of(4-chlorophenyl)[2-chloro-4-(3-chlorophenyl)-6quinolinyl]methanone(0.016 mol) and NaN₃ (0.024 mol) in DMF (50 ml) was stirred at 100° C.for 8 hours, brought to room temperature and poured out on ice. Theprecipitate was filtered off, washed with H₂O and taken up in CH₂Cl₂.The organic layer was separated, dried, filtered and the solvent wasevaporated. The residue was taken up in CH₃CN. The precipitate wasfiltered off and dried, yielding 5.1 g of intermediate (15) (76%).

EXAMPLE A9

Preparation of

A mixture of(4-chlorophenyl)[2-chloro4-(3-chlorophenyl)-6-quinolinyl]methanonemonohydrochloride (0.0349 mol) and hydrazinecarboxaldehyde (0.0524 mol)in 1-butanol (180 ml) was stirred and refluxed for the weekend. Thesolvent was evaporated. THF (100 ml) and HCl 3N (200 ml) were added. Themixture was stirred and refluxed for 3 hours. The mixture was cooled,poured out on ice, basified with NH₄OH, filtered over celite, washedwith EtOAc and decanted. The organic layer was dried (MgSO₄), filteredand the solvent was evaporated. The residue (11.8 g) was purified bycolumn chromatography over silica gel (eluent: CH₂Cl₂/CH₃OH/NH₄OH97/3/0.1; 20-45 μm). The pure fractions were collected and the solventwas evaporated. Yielding: 5 g of intermediate 16 (34%).

EXAMPLE A10

a) Preparation of

A mixture of 6-bromo-2-chloro-4-(3-chlorophenyl)quinoline (0.0276 mol)in THF (30 ml) was cooled to −70° C. under N₂ flow. BuLi 1.6N in hexane(0.033 mol) was added dropwise at −70° C. The mixture was stirred at−70° C. for 1 hour. A solution of 2,4difluorobenzaldehyde (0.0276 mol)in THF (100 ml) was added dropwise at −70° C. The mixture was stirred at−70° C. for 1 hour, hydrolized cold and extracted with EtOAc. Theorganic layer was separated, washed with H₂O, dried (MgSO₄), filteredand the solvent was evaporated. The residue was purified by columnchromatography over silica gel (eluent: CH₂Cl₂/CH₃OH 99.5/0.5; 20-45μm). The pure fractions were collected and the solvent was evaporated.Yielding: 5.2 g of intermediate (17) (46%).b) Preparation of

MnO₂ (0.0374 mol) was added to a mixture of intermediate (17) (0.0125mol) in dioxane (50 ml). The mixture was stirred at 80° C. overnight,brought to room temperature, filtered over celite and washed withCH₂Cl₂. The filtrate was evaporated. Yielding: 5 g of intermediate (18)(96%).

EXAMPLE A11

a) A mixture of (4-chlorophenyl)(4-nitrophenyl)-methanone (0.0382 mol),1,2-ethanediol (0.0764 mol) and p-toluenesulfonic acid (0.19 mol) intoluene (15 ml) was stirred and refluxed in a Dean Stark apparatus for24 h. The mixture was washed with K₂CO₃ 10% and then with water. Theorganic layer was dried, filtered off and evaporated, yielding (98%) ofintermediate 19.

b) Intermediate 19 and then 3chloro-benzeneacetonitrile (0.147 mol) wereadded to a mixture of NaOH (0.409 mol) in methanol (100 ml). The mixturewas stirred and refluxed. Ice and then ethanol were added. The mixturewas allowed to crystallize out. The precipitate was filtered, washedwith ethanol and dried, yielding intermediate 20.

c) TiCl₃ (15% in H₂O; 308 ml) was added at room temperature to a mixtureof intermediate 20 (0.124 mol) in THF (308 ml). The mixture was stirredat room temperature for 48 hr. Water was added and the mixture wasextracted with CH₂Cl₂. The organic layer was separated, washed withK₂CO₃ 10%, dried, filtered and the solvent was evaporated, yieldingintermediate 21.

d) A mixture of intermediate 21 (0.097 mol) and 2-propanone (0.291 mol)in H₂SO₄ (1 ml) and acetic acid (100 ml) was stirred and refluxed for 24hours. The mixture was poured out on ice and NH₄OH and extracted twicewith CH₂Cl₂. The combined organic layer was separated, dried, filteredand the solvent was evaporated. The residue was taken up in CH₃CN,filtered off and dried, yielding 24 g (63%) of intermediate 22.

e) A mixture of intermediate 22 (0.0255 mol), 1,2-ethanediol (0.102 mol)and p-toluene sulfonic acid (0.0305 mol) in toluene (200 ml) was stirredand refluxed for 16 hours. The mixture was poured out on ice. K₂CO₃ 10%was added and the mixture was extracted twice with CH₂Cl₂. The combinedorganic layer was dried, filtered and the solvent was evaporated. Theresidue was crystallized from DIPE and pentane. The precipitate wasfiltered off and dried, yielding 9 g (80%) of intermediate 23.

f) A mixture of intermediate 23 (0.0206 mol) and SeO₂ (0.0206 mol) indioxane (100 ml) and H₂O (10 ml) was stirred and refluxed for 3 hours.The mixture was filtered warm over celite, washed with H₂O and withCH₂Cl₂ and decanted. The organic layer was dried, filtered and thesolvent was evaporated. The residue was purified by columnchromatography over silica gel (eluent: cyclohexane/EtOAc 80/20). Thepure fractions were collected and the solvent was evaporated, yielding4.68 g (50%) of intermediate 24.

g) A mixture of intermediate 24 (0.0104 mol) and4-methyl-benzenesulfonic acid, hydrazide (0.0114 mol) in methanol (60ml) was stirred at 50° C. overnight. The mixture was allowed to cool toroom temperature. The precipitate was filtered off, washed with ethanoland dried, yielding 4.09 g (85%) of intermediate 25.

h) A mixture of intermediate 25 (0.00865 mol) in HCl 6N (40 ml) and THF(140 ml) was stirred at room temperature for 48 hours. The mixture waspoured out on ice, basified with K₂CO₃ 10% and extracted with EtOAc. Theorganic layer was separated, dried, filtered and the solvent wasevaporated. The residue was purified by column chromatography oversilica gel (eluent: CH₂Cl₂/EtOAc 95/5). The pure fractions werecollected and the solvent was evaporated, yielding 1.2 g (33%)intermediate 26.

i) NaBH₄ (0.00344 mol) was added at room temperature to a solution ofintermediate 26 (0.00286 mol) in THF (10 ml) and methanol (10 ml). Themixture was stirred at room temperature for 15 min. H₂O was added andthe mixture was extracted with CH₂Cl₂. The organic layer was separated,dried, filtered and the solvent was evaporated, yielding 1.2 g ofintermediate 27.

j) A mixture of intermediate 27 (0.00286 mol) in CH₂Cl₂ (20 ml) wasstirred at 0° C. under N₂. SOCl₂ (5 ml) was added. The mixture wasstirred at 10° C. for 1 hour. solvent was evaporated, yieldingintermediate 28.

EXAMPLE A12

a) A mixture of intermediate 29, prepared analogous to example A1(0.0727 mol), in acetic acid (90 ml) and xylene (300 ml) was stirred andfor 72 h. The solvent was evaporated. The residue was taken in CH₂Cl₂,K₂CO₃ 10% was added and filtered over celite. The organic layer wasdecanted, dried, filtered and the solvent was evaporated. The residuewas purified by column chromatography over silica gel (eluent:CH₂Cl₂/CH₃OH 99/1). The pure fractions were collected and the solventwas evaporated. The residue was recrystallized from CH₃CN. Theprecipitate was filtered off and dried, yielding 6.7 g (56%)intermediate 30.

b) NaBH₄ (0.0086 mol) was added portionwise at 10° C. to a solution ofintermediate 30 (0.00719 mol) in methanol (30 ml) and THF (20 ml). Themixture was stirred at ° C. for 15 min. Water was added and the mixturewas concentrated. The concentrate was taken up in CH₂Cl₂. The organiclayer was separated, washed with water, dried, filtered and the solventwas evaporated. The residue was crystallized from 2-propanone. Theprecipitate was filtered off and dried, yielding 1.45 g (48%) ofintermediate 31.

c) A mixture of intermediate 30 (0.0096 mol) in formamide (19 ml) andacetic acid (20 ml) was stirred at 160° C. for 48 hours. The mixture wascooled. Ice was added. The mixture was extracted with CH₂Cl₂ anddecanted. The organic layer was dried, filtered and the solvent wasevaporated, yielding 4.2 g of intermediate 32.

d) A mixture of intermediate 32 (0.0096 mol) in HCl 3N (60 ml) and2-propanol (60 ml) was stirred at 80° C. for 2.5 hours. The mixture waspoured out on ice, basified with NH₄OH and extracted with CH₂Cl₂. Theorganic layer was separated, dried, filtered and the solvent wasevaporated. The residue was purified by column chromatography oversilica gel (eluent: CH₂Cl₂/CH₃OH/NH₄OH 98/2/0.1). The pure fractionswere collected and the solvent was evaporated. The residue wascrystallized from CH₃CN and DIPE. The precipitate was filtered off anddried, yielding 1.15 g (29%) of intermediate 33.

EXAMPLE A13

A mixture of intermediate 29 (0.0472 mol) in acetic acid (30 ml) andxylenes (200 ml) was stirred and refluxed for 48 hr. The solvent wasevaporated. The residue was taken up in CH₂Cl₂, washed with K₂CO₃ 10%,dried, filtered and the solvent was evaporated. The residue was purifiedby column chromatography over silica gel (eluent: CH₂Cl₂/CH₃OH/NH₄OH99/1/0.1). The pure fractions were collected and the solvent wasevaporated, yielding 15.6 g (75%) of intermediate 34.

B. Preparation of the Final Compounds.

EXAMPLE B1

A mixture of intermediate (2) (0.0207 mol) in acetic acid (10 ml) andmixed xylenes (100 ml) was stirred and refluxed for 12 hours and cooled.The mixture was evaporated and the residue was taken up in water,basified with NaOH (2N) and extracted with CH₂Cl₂. The residue waspurified by column chromatography over silica gel. The pure fractionswere collected and evaporated. The residue was converted into theethanedioic acid salt (2:3) in C₂H₅OH/CH₃OH/2-propanone, yielding 3.5 g(30%) of(±)-7-[(4fluorophenyl)(1H-imidazol-1-yl)methyl]-5-phenylimidazo[1,2-a]quinolineethanedioate(2:3).hemihydrate; mp. 204.3° C. (comp. 3).

EXAMPLE B2

Preparation of

A mixture of intermediate (4) (0.0019 mol) in ethanol (5 ml) was stirredat 80° C. for 5 hours, then cooled and taken up in CH₂Cl₂. The organicsolution was washed with K₂CO₃ (10%), dried, filtered and the solventwas evaporated. The residue was purified by column chromatography oversilica gel. The pure fractions were collected and the solvent wasevaporated. The residue was crystallized from 2-propanone and DIPE. Theprecipitate was filtered off and dried yielding 0.14 g (12%) of compound(95); mp. 143° C.

EXAMPLE B3

A mixture of intermediate (5) (0.029 mol) and formylhydrazine (0.043mol) in 1-butanol (150 ml) was stirred and refluxed for 48 hours. Themixture was evaporated, the residue was taken up in CH₂Cl₂ and washedwith water. The organic layer was dried, filtered off and evaporated.The residue was purified by column chromatography over silica gel. Thepure fractions were collected and evaporated. The residue was dissolvedin 2-propanone and converted into the ethanedioic acid salt (2:3)yielding 4.4 g (26.1%) of(±)-7-[(4-chlorophenyl)-1H-imidazol-1-ylmethyl]-5-phenyl[1,2,4]-triazolo[4,3-a]quinolineethanedioate(2:3).hemihydrate (comp. 5).

EXAMPLE B4

A mixture of intermediate (7) (0.0071 mol) and triethyl orthoacetate(0.0086 mol) in n-butanol (35 ml) was stirred at 100° C. overnight. Thesolvent was evaporated. The residue was taken up in CH₂Cl₂, washed withH₂O and with a saturated NaCl solution, dried, filtered and the solventwas evaporated. The residue was purified by column chromatography oversilica gel. The pure fractions were collected and the solvent wasevaporated. The residue was crystallized from 2-propanone. Theprecipitate was filtered off and dried yielding 1.95 g (53%) of(±)-5-(3-chlorophenyl)-α-(4-chlorophenyl)-1-methyl-α-(1-methyl-1H-imidazol-5-yl)-1,2,4triazolo[4,3-a]quinoline-7-methanol(comp. 19).

EXAMPLE B5

Preparation of

Cyanogen bromide (0.00815 mol) was added portionwise at 5° C. to asolution of intermediate (7) (0.00815 mol) in methanol (80 ml). Themixture was stirred at 60° C. for 10 minutes. and then brought to roomtemperature. The solvent was evaporated. The residue was taken up inK₂CO₃ 10%, filtered off, washed with K₂CO₃ (10%) and with H₂O and dried.The residue was purified by column chromatography over silica gel. Thepure fractions were collected and the solvent was evaporated. Theresidue was crystallized from THF)/DIPE. The precipitate was filteredoff and dried yielding 1.45 g (34%) of compound (20).

EXAMPLE B6

Preparation of

1,1′-carbonylbis-1H-imidazole (0.0055 mol) was added at room temperatureto a solution of intermediate (7) (0.00367 mol) in THF (30 ml) and themixture was stirred at room temperature for 30 min. Ice and then waterwere added, and the mixture was extracted twice with EtOAc. The combinedorganic layer was separated, dried, filtered and the solvent wasevaporated. The residue was taken up in CH₂Cl₂. The precipitate wasfiltered off and dried. The residue was crystallized from THF/diethylether. The precipitate was filtered off and dried, yielding 0.85 g (45%)of compound (22).

EXAMPLE B7

A mixture of intermediate (5) (0.029 mol) and ethyl carbazate (0.0436mol) in 1-butanol (150 ml) was stirred and refluxed for one night. Themixture was evaporated in vacuo, the residue was taken up in CH₂Cl₂ andwashed with water. The organic layer was dried, filtered off andevaporated. The residue was purified by column chromatography oversilica gel. The pure fractions were collected and evaporated. Theresidue was dissolved in 2-propanone and converted into the ethanedioicacid salt (1:1) yielding 1 g (6.3%) of(±)-7-[(4-chlorophenyl)-1H-imidazol-1-ylmethyl]-5-phenyl[1,2,4]triazolo[4,3-a]quinolin-1(2H)-oneethanedioate(1:1).hemihydrate; mp. 198.3° C. (comp. 7).

EXAMPLE B8

A mixture of intermediate (9) (0.006 mol) and sodium azide (0.018 mol)in DMF (20 ml) was stirred at 140° C. for 4 hours. The mixture wascooled to room temperature and poured out into ice water. Theprecipitate was filtered off, washed with H₂O and taken up in CH₂Cl₂.The organic solution was dried, filtered and the solvent was evaporated.The residue was crystallized from CH₃CN and 2-propanone. The precipitatewas filtered off and dried yielding 1.2 g (38.2%) of(±)-5-(3-chlorophenyl)-α-(4-chlorophenyl)-α-(1-methyl-1H-imidazol-5-yl)tetrazolo[1,5-a]quinazoline-7-methanol;mp. 139° C. (comp. 29).

EXAMPLE B9

A mixture of intermediate (11) (0.0116 mol) and p-toluenesulfonhydrazide(0.0128 mol) in CH₃OH (60 ml) was stirred at 60° C. for 2 hours and thenbrought to room temperature. H₂O was added. The mixture was extractedwith CH₂Cl₂. The organic layer was separated, dried, filtered and thesolvent was evaporated. The residue was purified by columnchromatography over silica gel. Two pure fractions were collected andtheir solvents were evaporated. The desired fraction was crystallizedfrom 2-propanone and CH₃CN. The precipitate was filtered off and driedyielding 1.25 g (21%) of(±)-5-(3-chlorophenyl)-α-(4-chlorophenyl)-α-(1-methyl-1H-imidazol-5-yl)-[1,2,3]triazolo[1,5-a]quinoline-7-methanol;mp. 222° C. (comp. 26).

EXAMPLE B10

A mixture of compound (29) (0.008 mol) in methanol (60 ml) was cooled to5° C. Sodium tetrahydroborate (0.008 mol) was added portionwise. Themixture was stirred at 5° C. for 1 hour, hydrolized, extracted withCH₂Cl₂ and decanted. The organic layer was dried, filtered and thesolvent was evaporated. The residue was crystallized from 2-propanone.The precipitate was filtered off and dried yielding 1.8 g (44.6%) of(±)5-(3-chlorophenyl)-α-(4-chlorophenyl)4,5-dihydro-α-(1-methyl-1H-imidazol-5-yl)tetrazolo[1,5-a]quinazoline-7-methanol;mp. 212° C. (comp. 30).

EXAMPLE B11

A dispersion of sodium hydride (80%) in a mineral oil (0.0083 mol) wasadded at 5° C. under N₂ flow to a mixture of intermediate (10) (0.007mol) in DMF (33 ml). The mixture was stirred at 5° C. for 30 min.Iodomethane (0.008 mol) was added. The mixture was stirred at 5° C. for30 minutes and then hydrolized. The precipitate was filtered off, washedwith H₂O and taken up in CH₂Cl₂. The organic solution was dried,filtered and the solvent was evaporated. The residue was purified bycolumn chromatography over silica gel. The pure fractions were collectedand the solvent was evaporated. The residue was crystallized from CH₃CNand DIPE. The precipitate was filtered off and dried, yielding 0.8 g(22%) of(±)-5-(3-chlorophenyl)-α-(4-chlorophenyl)-4,5-dihydro-4methyl-α-(1-methyl-1H-imidazol-5-yl)tetrazolo[1,5-a]quinazoline-7-methanol;mp. 235° C. (comp. 33).

EXAMPLE B12

Preparation of

A mixture of(±)5-(3-chlorophenyl)-α-(4-chlorophenyl)-α-(1-methyl-1H-imidazol-5-yl)tetrazolo[1,5-a]quinoline-7-methanol(0.005 mol) in formamide (10 ml) and acetic acid (20 ml) was stirred at160° C. for 5 hours, poured out on ice, basified with NH₄OH andextracted with CH₂Cl₂. The organic layer was separated, dried, filteredand the solvent was evaporated. The residue was purified by columnchromatography over silica gel. The pure fractions were collected andthe solvent was evaporated. The residue was crystallized from CH₃CN anddiethyl ether. The precipitate was filtered off and dried yielding 0.84g (35%) of compound (94); mp. 166° C.

EXAMPLE B13

Preparation of

Compound (29) (0.006 mol) was added at a low temperature to thionylchloride (30 ml). The mixture was stirred at 40° C. for 2 hours. Thesolvent was evaporated, yielding compound (31).

EXAMPLE B14

A mixture of 2-propanol and NH₃ (35 ml) was added dropwise quickly at 0°C. to a mixture of compound (31) (0.006 mol) in THF (35 ml). The mixturewas stirred at 5° C. for 30 min and then brought to room temperature.The solvent was evaporated. The residue was taken up in CH₂Cl₂ and H₂Oand the mixture was decanted. The organic layer was dried, filtered andthe solvent was evaporated. The residue was purified by columnchromatography over silica gel. The pure fractions were collected andthe solvent was evaporated. The residue was crystallized from CH₂Cl₂ andDIPE. The precipitate was filtered off and dried yielding 0.6 g (20%) of(±)-5-(3-chlorophenyl)-α-(4-chlorophenyl)-α-(1-methyl-1H-imidazol-5-yl)tetrazolo[1,5-a]quinazoline-7-methanamine;mp. 159° C. (comp. 32).

EXAMPLE B15

n-Butyllithium (0.0129 mol) was added slowly at −70° C. under N₂ flow toa solution of 1-methylimidazole (0.0129 mol) in THF (25 ml). The mixturewas stirred for 30 min. Chlorotriethylsilane (0.0129 mol) was added. Themixture was allowed to warm to room temperature and then cooled to −70°C. n-Butyllithium (0.0129 mol) was added. The mixture was stirred at−70° C. for 1 hour, then allowed to warm to −15° C. and cooled to −70°C. A solution of(±)-α-(4-chlorophenyl)-5-phenylimidazo[1,2-a]quinoline-7-methanone(0.0107 mol) in THF (12 ml) was added. The mixture was stirred at −70°C. for 1 hour. Water was added The mixture was extracted with EtOAc. Theorganic layer was separated, dried, filtered and the solvent wasevaporated. The residue was purified by column chromatography oversilica gel. The pure fractions were collected and the solvent wasevaporated. The residue was crystallized from 2-propanone. Theprecipitate was filtered off and dried, yielding 0.9 g (18%) of(±)-α-(4-chlorophenyl)-α-(1-methyl-1H-imidazol-5-yl)-5-phenylimidazo[1,2-a]quinoline-7-methanol(compound 11).

EXAMPLE B16

Preparation of

A mixture of intermediate 28 (0.00286 mol) and 1H-imidazole (0.017 mol)in CH₃CN (20 ml) was stirred and refluxed for 48 hours and then broughtto room temperature. H₂O was added. The mixture was extracted withCH₂Cl₂. The organic layer was separated, dried, filtered and the solventwas evaporated. The residue was purified by column over silica gel(eluent: CH₂Cl₂/CH₃OH/NH₄OH 98/2/0.1). The pure fractions were collectedand the solvent was. The residue was crystallized from CH₃CN and DIPE.The precipitate was filtered off and dried, yielding 0.55 g compound 25(40%).

EXAMPLE B17

Preparation of

H₂SO₄ conc. (0.1 ml) was added dropwise to CH₃CN (5 ml). Then compound(142) (0.00042 mol) was added portionwise. The mixture was stirred at80° C. for 2 hours, brought to room temperature and poured out into icewater. EtOAc was added The mixture was basified with K₂CO₃ 10% andextracted with EtOAc. The organic layer was separated, washed with H₂O,dried, filtered and the solvent was evaporated. The residue was purifiedby column chromatography over silica gel (eluent: CH₂Cl₂/CH₃OH/NH₄OH96/4/0.1; 15-40 μm). The pure fractions were collected and the solventwas evaporated. This fraction was crystallized from CH₃CN and DIPE. Theprecipitate was filtered off and dried, yielding 0.11 g of compound(144) (44%).

EXAMPLE B18

A mixture of compound 53 (0.00464 mol) in SOCl₂ (30 ml) was stirred at60° C. for 6 hours. The solvent was evaporated, yielding compound 76.

EXAMPLE B19

A mixture of compound 16 (0.0022 mol) in 1,2-ethanediol (15 ml) andH₂SO₄ (conc.) (5 drops) was stirred and refluxed at 125° C. for 6 hours.K₂CO₃ 10% was added and the mixture was extracted with CH₂Cl₂. Theorganic layer was separated, dried, filtered, and the solvent wasevaporated. The residue was purified by column chromatography oversilica gel (eluent: toluene/2-propanol/NH₄OH 88/12/0.8). The purefractions were collected and the solvent was evaporated. The residue wasconverted into the ethanedioic acid salt (1:1) in 2-propanone andcrystallized from CH₃CN/2-propanone. The precipitate was filtered off,washed with diethyl ether and dried. yielding 0.5 g of compound 41(35%); mp. 150° C.

EXAMPLE B20

4-(3-chlorophenyl)-α⁶-(4-chlorophenyl)-2-hydrazino-α⁶-(1-methyl-1H-imidazol-5-yl)-3,6-quinolinedimethanol(0.00371 mol) was added to HCl 1N (25 ml) and stirred at roomtemperature. A solution of NaNO₂ (0.00408 mol) in H₂O (5 ml) was addeddropwise and the resulting reaction mixture was stirred and refluxed forone hour. The mixture was allowed to cool to room temperature, thenpoured out into ice-water and the precipitate was filtered off, washedwith water, washed with diethyl ether and dried, yielding 1.95 g ofcompound 82 (92%; mp: >280° C.).

EXAMPLE B21

HCl 3N (20 ml) was added dropwise to a solution of compound 51 (0.0123mol) in H₂O (80 ml) (until pH=2). The mixture was stirred for 1 hour.The precipitate was filtered off and dried, yielding 5 g of compound 53(70%); mp. >260° C.

EXAMPLE B22

NH₂CH₃ (2.5 ml) was added dropwise at room temperature to a mixture ofcompound 25 and compound 47 (0.0086 mol) in THF (45 ml). The mixture wasstirred at 40° C. for 30 min, hydrolized and extracted with CH₂Cl₂. Theorganic layer was separated, dried, filtered and the solvent wasevaporated. The residue was purified by column chromatography oversilica gel (eluent: toluene/2-propanol/NH₄OH 85/15/1). Three fractionswere collected and their solvents were evaporated. Fraction 1 wascrystallized from CH₃CN and DIPE. The precipitate was filtered off anddried, yielding 0.4 g of compound 48 (9%); mp. 167° C. Fraction 2 wascrystallized from CH₃CN and diethyl ether. The precipitate was filteredoff and dried, yielding 0.6 g of compound 49 (13%); mp. 206° C.

EXAMPLE B23

(R)-1-(1-isocyanatoethyl)naphthalene (0.0039 mol) was added to a mixtureof compound 18 (0.00196 mol) in THF (10 ml). The mixture was stirred andrefluxed for 18 hours, hydrolized and extracted with CH₂Cl₂. The organiclayer was separated, dried, filtered and the solvent was evaporated. Theresidue was purified by column chromatography over silica gel (eluent:cyclohexane/2-propanol/NH₄OH 70/30/1). The pure fractions were collectedand the solvent was evaporated. The residue was crystallized from CH₃CNand DIPE. The precipitate was filtered off and dried, yielding 0.55 g ofcompound 135 (40%).

EXAMPLE B24

Compound 18 (0.008 mol) was purified and separated into its enantiomersby chiral column chromatography over Chiralcel OD (eluent: ethanol100%). Two pure fractions were collected and their solvents wereevaporated. Fraction 1 was converted into the ethanedioic acid salt(1:1). The precipitate was filtered off and dried, yielding 1.59 g ofcompound 28 (34%); mp. 180° C. Fraction 2 was converted into theethanedioic acid salt (1:1) and crystallized from ethanol. Theprecipitate was filtered off and dried, yielding 1.85 g of compound 27(39%); mp. 172° C.

EXAMPLE B25

K₂CO₃ (0.096 mol) was added at 5° C. to a mixture of hydroxylaminehydrochloride (0.09 mol) in H₂O (10 ml). The mixture was stirred for 15min. A solution of compound 69 (0.003 mol) in THF (15 ml) was addeddropwise. The mixture was stirred at 5° C. for 30 min. Ice water wasadded and the mixture was extracted with CH₂Cl₂. The organic layer wasseparated, dried, filtered and the solvent was evaporated. The residuewas purified by column chromatography over silica gel (eluent:CH₂Cl₂/CH₃OH/NH₄OH 95/5/0.3). The pure fractions were collected and thesolvent was evaporated. The residue was crystallized from EtOAc. Theprecipitate was filtered off and dried, yielding 0.17 g of compound 98(11%); mp. 191° C.

EXAMPLE B26

NH₄OH conc. (10 ml) was added dropwise at 5° C. to a mixture of compound76 (0.00464 mol) in THF (20 ml). The mixture was stirred at roomtemperature for 2 hours, poured out on ice and extracted with CH₂Cl₂.The organic layer was separated, dried, filtered and the solvent wasevaporated. The residue was purified by column chromatography oversilica gel (eluent: CH₂Cl₂/CH₃OH/NH₄OH 95/5/0.1). Two pure fractionswere collected and their solvents were evaporated. Fraction 1 wascrystallized from CH₃CN and DIPE. The precipitate was filtered off anddried, yielding 0.55 g of compound 77 (21%); mp. >250° C. Fraction 2 waspurified by column chromatography over silica gel (eluent:CH₂Cl₂/CH₃OH/NH₄OH 95/5/0.5; 20-45 μm). The pure fractions werecollected and the solvent was evaporated. The residue was crystallizedfrom CH₃CN. The precipitate was filtered off and dried, yielding 0.17 gof compound 80 (6%); mp. >250° C.

EXAMPLE B27

Methanamine (30 ml; 40% in H₂O) was added to a mixture of compound 119(0.004 mol) in THF (20 ml). The mixture was stirred for 1 hour. K₂CO₃10% was added and the mixture was extracted with CH₂Cl₂. The organiclayer was separated, dried, filtered and the solvent was evaporated. Theresidue was purified by column chromatography over silica gel (eluent:CH₂Cl₂/CH₃OH/NH₄OH 90/10/0.1 and 80/20/0.1). The pure fractions werecollected and the solvent was evaporated. The residue was crystallizedfrom THF and diethyl ether. The precipitate was filtered off and dried,yielding 1.1 g of compound 121 (48%); mp. 224° C.

EXAMPLE B28

LiAlH₄ (0.00663 mol) was added at 5° C. under N₂ flow to THF (30 ml).Then compound 52 (0.00331 mol) was added portionwise. The mixture wasstirred at room temperature for 1 hour. EtOAc was added. The mixture washydrolized cold, filtered over celite and washed with EtOAc. Thefiltrate was extracted with EtOAc. The organic layer was separated,washed with H₂O, dried, filtered and the solvent was evaporated. Theresidue was purified by column chromatography over silica gel (eluent:cyclohexane/2-propanol/NH₄OH 80/20/1). The pure fractions were collectedand the solvent was evaporated. This fraction was crystallized from2-propanone and diethyl ether. The precipitate was filtered off anddried, yielding 0.98 g of compound 75 (51%).

The following compounds were prepared analogous to the one of the aboveexamples (the example number analogous to which they were prepared isindicated between square brackets after the compound number).

Ethanedioate (2:3) Hydrate (2:1) Comp 1[B1]; mp. 225° C.

Ethanedioate (2:3) Hydrate (1:1) Comp 2[B1]; mp. 203° C.

Ethanedioate (2:3) Hydrate (2:1) Comp 3[B1]; mp. 204° C.

Ethanedioate (2:3) Hydrate (2:1) Comp 4[B1]; mp. 202° C.

Ethanedioate (2:3) Hydrate (2:1) Comp 5[B3]

Comp 6[B3]; mp 259° C.

Ethanedioate (1:1) Hydrate (2:1) Comp 7[B7]; mp. 198° C.

Ethanedioate (1:1) Comp 8[B20]

Ethanedioate (2:3) Comp 9[B3]; mp. 194° C.

Comp 10[B1]; mp. 131° C.

Comp 11[B15]

Comp 12[B15]

Hydrochloride (1:2) Comp 13[B13]

Ethanedioate (1:2) Hydrate (2:3) Comp 14[B14]

Ethanedioate (1:1) Comp 15[B15]

Comp 16[B8]

Hydrochloride (1:1) Comp 17[B13]

Comp 18[B14]

Comp 19[B4]

Comp 20[B5]

Comp 21[B4]

Comp 22[B6]

Hydrochloride (1:1) Comp 23[B13]

Comp 24[B14]

Comp 25[B16]; mp. 242° C.

Comp 26[B9]; mp. 222° C.

(B) Ethanedioate (1:1) Comp 27[B24]; mp 172° C.

(A) Ethanedioate (1:1) Comp 28[B24]; mp. 180° C.

Comp 29[B8]; mp. 139° C.

Comp 30[B10]; mp. 212° C.

Hydrochloride (1:1) Comp 31[B13]

Comp 32[B14]; mp. 159° C.

Comp 33[B11]; mp. 235° C.

Hydrochloride (1:1) Comp 34[B13]

Comp 35[B14]

Hydrochloride (1:1) Comp 36[B13]

Comp 37; mp. 237° C.[B14]

Comp 38[B3]; mp. >260° C.

Comp 39[B1]; mp. 200° C.

Comp 40[B17]; mp. >260° C.

Ethanedioate (1:1) Hydrate (1:1) Comp 41[B19]; mp. 150° C.

Comp 42[B25[; mp. 205° C.

Comp 43[B8]; mp. >260° C.

Hydrochloride (1:1) Comp 44[B13]

Comp 45[B14]; mp. 217° C.

Comp 46[B25]; mp. 214° C.

Hydrochloride (1:1) Comp 47[B13]

Comp 48[B14]; mp. 167° C.

Comp 49[B22]; mp. 206° C.

Comp 50[B8]; mp. 255° C.

Comp 51[B8]

Comp 52[B8]; mp. >260° C.

Hydrochloride (1:1) Comp 53[B21]; mp. >260° C.

Comp 54[B8]

Comp 55[B8]; mp. 245° C.

Comp 56[B8]; mp. 204° C.

Hydrate (1:1) Comp 57[B3]

Hydrochloride (1:1) Comp 58[B13]

Comp 59[B14]; mp. 131° C.

Hydrochloride (1:1) Comp 60[B13]

Hydrate (1:1) Comp 61[B14]; mp. 199° C.

Comp 62[B8]; mp. 218° C.

Hydrochloride (1:1) Comp 63[B13]

Comp 64[B14]; mp. >260° C.

Hydrochloride (1:1) Comp 65[B13]

Comp 66[B14]; mp. 213° C.

Comp 67[B8]; mp. 222° C.

Comp 68[B8]; mp. >260° C.

Hydrochloride (1:1) Comp 69[B13]

Comp 70[B14]; mp. 231° C.

Hydrochloride (1:1) Comp 71[B13]

Comp 72[B14]; mp. >260° C.

Hydrochloride (1:1) Comp 73[B13]

Comp 74[B14]; mp. 163° C.

Comp 75[B28]; mp. 215° C.

Hydrochloride (1:1) Comp 76[B18]

Comp 77[B26]; mp. >250° C.

Hydrochloride (1:1) Comp 78[B13]

Comp 79[B14]; mp. 216° C.

Comp 80[B26]; mp. >250° C.

Comp 81[B20]; mp. 280° C.

Hydrochloride (1:1) Comp 82[B20]; mp. >280° C.

Comp 83[B8]; mp. 270° C.

Hydrate (1:1) Comp 84[B2]

Comp 85[B15]

Comp 86[B8]; mp. 260° C.

Hydrochloride (1:1) Comp 87[B13]

Comp 88[B25]; mp. 220° C.

Comp 89[B25]; mp. 157° C.

Hydrochloride (1:2) Comp 90[B13]

Hydrate (1:1) Comp 91[B14]; mp. 173° C.

Hydrochloride (1:2) Comp 92[B13]

Ethanedioate (2:5) Hydrate (1:2) Comp 93[B14]; mp. 208° C.

Comp 94[B12]; mp. 166° C.

Comp 95[B2]; mp. 243° C.

Hydrochloride (1:1) Comp 96[B13]

Comp 97[B14]; mp. 281° C.

Comp 98[B25]; mp. 191° C.

Comp 99[B25]; mp. 280° C.

Comp 100[B25]; mp. 215° C.

Comp 101[B25]; mp. 218° C.

Comp 102[B17]; mp. 241° C.

Comp 103[B20]; mp. 233° C.

Comp 104[B8]; mp. 255° C.

Comp 105[B20]; mp. 239° C.

Comp 106[B8]; mp. 263° C.

Comp 107[B17]; mp. 207° C.

Comp 108[B25]; mp. 290° C.

Comp 109[B8]; mp. 232° C.

Comp 110[B17]; mp. 232° C.

Comp 111[B17]; mp. 197° C.

Comp 112[B8]; mp. 220° C.

Comp 113[B8]; mp. 246° C.

Comp 114[B17]; mp. 236° C.

Comp 115[B17]; mp. 245° C.

Comp 116[B17]; mp. 210° C.

Comp 117[B17]; mp. 238° C.

Comp 118[B17]; mp. 223° C.

Sulfate (2:1) Comp 119[B17]

Comp 120[B27]; mp. 206° C.

Comp 121[B27]; mp. 224° C.

Comp 122[B17]; mp. >300° C.

Comp 123[B17]; mp. 243° C.

Comp 124[B17]; mp. 286° C.

Hydrate (1:1) Comp 125[B17]; mp. 235° C.

Comp 126; mp. 270° C.

Comp 127[B17]; mp. 259° C.

[R(R*, S*)] + [S(R*, R*)] Comp 128[B23]; mp. 187° C.

Comp 129[B17]; mp. 241° C.

Comp 130[B8]; mp. 198° C.

Hydrochloride (1:1) Comp 131[B13]

Comp 132[B14]; mp. 260° C.

Comp 133[B25]; mp. 228° C.

Comp 134[B17]; mp. 260° C.

[R(R*, R*)] + [S(R*, S*)] Comp 135[B23]; mp. 230° C.

Comp 136[B17]; mp. 210° C.

Hydrate (1:1) Comp 137[B17]; mp. 217° C.

Comp 138[B8]; mp. 270° C.

Hydrate (1:1) Comp 139[B17]; mp. 185° C.

Comp 140[B8]

Comp 141[B17]

Comp 142[B8]; mp. 212° C.

Comp 143[B8]; mp. >260° C.

Comp 144[B17]

Comp 145[B17]

Comp 146[B15]

Comp 147[B17]

Comp 148[B8]

Comp 149

Comp 150[B8]

Comp 151[B17]

Comp 152[B17]

Comp 153[B8]

Comp 154[B17]

Comp 155[B8]C. Pharmacological Example.

EXAMPLE C.1 “In Vitro Assay for Inhibition of Farnesyl ProteinTransferase”

An in vitro assay for inhibition of farnesyl transferase was performedessentially as described in WO 98/40383, pages 33-34.

EXAMPLE C.2 “Ras-Transformed Cell Phenotype Reversion Assay”

The ras-transformed cell phenotype reversion assay was performedessentially as described in WO 98/40383, pages 34-36.

EXAMPLE C.3 “Farnesyl Protein Transferase Inhibitor Secondary TumorModel”

The farnesyl protein transferase inhibitor secondary tumor model wasused as described in WO 98/40383, page 37.

EXAMPLE C.4 “Geranylgeranyltransferase Type I Assay”

Background: The enzyme GGTase I catalyzes the covalent attachment of aC-20 geranylgeranyl moiety derived from geranylgeranyl pyrophosphate tothe K-ras oncogene product p21^(K-ras). The geranylgeranylation proceedsvia formation of a thioether linkage to a single, specific cysteineresidue contained in a cys-A-A-X motif wherein A represents neutralamino acids and X represents a C-terminal leucine or methionine.Farnesylation of H,N, and K-ras isoforms by farnesyl protein transferaseis required for activation and attachment of p21^(ras) to plasmamembranes. However, the K-ras isoform, which is the dominant isoform ofras in human tumors, is also isoprenylated by GGTase I. Therefore,inhibitors of GGTase I may inhibit the aberrant growth of K-rastransformed human tumors which are resistant to proteinfarnesyltransferase inhibitors.

Methods: Compounds were screened in vitro using GGTase I enzyme preparedfrom Kirsten virus transformed human osteosarcoma (KHOS) cells. Theassay measures the covalent attachment of radioactivity from[³H]-geranylgeranyl pyrophosphate to the K-ras peptide substratebiotinKKKKKKSKTLCVIM or biotin YRASNRSCAIL substrate.

Measurements: Percent control GGTase I activity.

Derived Variables: Control enzyme activity=[CPM ³H-geranylgeranylpeptide product in the presence of vehicle solvent]

Test compound concentration=10 μM. Test compound % control activity=(CPM³H-geranylgeranyl peptide product in the presence of testcompound/control enzyme activity)×100%

Standard Conditions: Compounds were dissolved in DMSO at a concentrationof 20 mM. Further dilutions were prepared in DMSO. The finalconcentration of DMSO in the assay medium was 10%. The compoundconcentration tested for screening was 10 μM.

D. Composition Example: Film-coated Tablets

Preparation of Tablet Core

A mixture of 100 g of a compound of formula (I), 570 g lactose and 200 gstarch is mixed well and thereafter humidified with a solution of 5 gsodium dodecyl sulfate and 10 g polyvinyl-pyrrolidone in about 200 ml ofwater. The wet powder mixture is sieved, dried and sieved again. Thenthere are added 100 g microcrystalline cellulose and 15 g hydrogenatedvegetable oil. The whole is mixed well and compressed into tablets,giving 10.000 tablets, each comprising 10 mg of a compound of formula(I).

Coating

To a solution of 10 g methyl cellulose in 75 ml of denaturated ethanolthere is added a solution of 5 g of ethyl cellulose in 150 ml ofdichloromethane. Then there are added 75 ml of dichloromethane and 2.5ml 1,2,3-propanetriol. 10 g of polyethylene glycol is molten anddissolved in 75 ml of dichloromethane. The latter solution is added tothe former and then there are added 2.5 g of magnesium octadecanoate, 5g of polyvinyl-pyrrolidone and 30 ml of concentrated colour suspensionand the whole is homogenated. The tablet cores are coated with the thusobtained mixture in a coating apparatus.

1. A method for inhibiting the abnormal growth of cells in which the rasoncogene is activated, in a mammal in need thereof, comprisingadministering to the mammal an effective amount of a compound of formula(I)

or a pharmaceutically acceptable acid addition salt or astereochemically isomeric form thereof, wherein ═X¹—X²—X³— is atrivalent radical of formula ═N—CR⁶═CR⁷— (x-1), ═CR⁶—CR⁷═CR⁸— (x-6),═N—N═CR⁶— (x-2), ═CR⁶—N═CR⁷— (x-7), ═N—NH—C(═O)— (x-3), ═CR⁶—NH—C(═O)—(x-8), or ═N—N═N— (x-4), ═CR⁶—N═N— (x-9); ═N—CR⁶═N— (x-5),

wherein each R⁶, R⁷ and R⁸ are independently hydrogen, C₁₋₄alkyl,hydroxy, C₁₋₄alkyloxy, aryloxy, C₁₋₄alkyloxycarbonyl, hydroxyC₁₋₄alkyl,C₁₋₄alkyloxyC₁₋₄alkyl, mono- or di(C₁₋₄alkyl)aminoC₁₋₄alkyl, cyano,amino, thio, C₁₋₄alkylthio, arylthio or aryl; >Y¹—Y²— is a trivalentradical of formula>CH—CHR⁹—  (y-1),>C═N—  (y-2),>CH—NR⁹—  (y-3), or>C═CR⁹—  (y-4); wherein each R⁹ independently is hydrogen, halo,halocarbonyl, aminocarbonyl, hydroxyC₁₋₄alkyl, cyano, carboxyl,C₁₋₄alkyl, C₁₋₄alkyloxy, C₁₋₄alkyloxyC₁₋₄alkyl, C₁₋₄alkyloxycarbonyl,mono- or di(C₁₋₄alkyl)amino, mono- or di(C₁₋₄alkyl)aminoC₁₋₄alkyl, aryl;r and s are each independently 0, 1, 2, 3, 4 or 5; t is 0, 1, 2 or 3;each R¹ and R² are independently hydroxy, halo, cyano, C₁₋₆alkyl,trihalomethyl, trihalomethoxy, C₂₋₆alkenyl, C₁₋₆alkyloxy,hydroxyC₁₋₆alkyloxy, C₁₋₆alkylthio, C₁₋₆alkyloxyC₁₋₆alkyloxy,C₁₋₆alkyloxycarbonyl, aminoC₁₋₆alkyloxy, mono- or di(C₁₋₆alkyl)amino,mono- or di(C₁₋₆alkyl)aminoC₁₋₆alkyloxy, aryl, arylC₁₋₆alkyl, aryloxy orarylC₁₋₆alkyloxy, hydroxycarbonyl, C₁₋₆alkyloxycarbonyl, aminocarbonyl,aminoC₁₋₆alkyl, mono- or di(C₁₋₆alkyl)aminocarbonyl, or mono- ordi(C₁₋₆alkyl)aminoC₁₋₆alkyl; or two R¹ or R² substituents adjacent toone another on the phenyl ring independently form together a bivalentradical of formula—O—CH₂—O—  (a-1),—O—CH₂—CH₂—O—  (a-2),—O—CH═CH—  (a-3),—O—CH₂—CH₂—  (a-4),  —O—CH₂—CH₂—CH₂—  (a-5), or—CH═CH—CH═CH—  (a-6); R³ is hydrogen, halo, C₁₋₆alkyl, cyano,haloC₁₋₆alkyl, hydroxyC₁₋₆alkyl, cyanoC₁₋₆alkyl, aminoC₁₋₆alkyl,C₁₋₆alkyloxyC₁₋₆alkyl, C₁₋₆alkylthioC₁₋₆alkyl, aminocarbonylC₁₋₆alkyl,hydroxycarbonyl, hydroxycarbonylC₁₋₆alkyl,C₁₋₆alkyloxycarbonylC₁₋₆alkyl, C₁₋₆alkylcarbonylC₁₋₆alkyl,C₁₋₆alkyloxycarbonyl, aryl, arylC₁₋₆alkyloxyC₁₋₆alkyl, mono- ordi(C₁₋₆alkyl)aminoC₁₋₆alkyl; or a radical of formula—O—R¹⁰  (b-1),—S—R¹⁰  (b-2), or—NR¹¹R¹²  (b-3), wherein R¹⁰ is hydrogen, C₁₋₆alkyl, C₁₋₆alkylcarbonyl,aryl, arylC₁₋₆alkyl, C₁₋₆alkyloxycarbonylC₁₋₆alkyl, or a radical offormula -Alk-OR¹³ or -Alk-NR¹⁴R¹⁵; R¹¹ is hydrogen, C₁₋₆alkyl, aryl orarylC₁₋₆alkyl; R¹² is hydrogen, C₁₋₆alkyl, aryl, hydroxy, amino,C₁₋₆alkyloxy, C₁₋₆alkylcarbonylC₁₋₆alkyl, arylC₁₋₆alkyl,C₁₋₆alkylcarbonylamino, mono- or di(C₁₋₆alkyl)amino, C₁₋₆alkylcarbonyl,aminocarbonyl, arylcarbonyl, haloC₁₋₆alkylcarbonyl,arylC₁₋₆alkylcarbonyl, C₁₋₆alkyloxycarbonyl,C₁₋₆alkyloxyC₁₋₆alkylcarbonyl, mono- or di(C₁₋₆alkyl)aminocarbonylwherein the alkyl moiety may optionally be substituted by one or moresubstituents independently selected from aryl or C₁₋₃alkyloxycarbonyl,aminocarbonylcarbonyl, mono- or di(C₁₋₆alkyl)aminoC₁₋₆alkylcarbonyl, ora radical or formula -Alk-OR¹³ or -Alk-NR¹⁴R¹⁵; wherein Alk isC₁₋₆alkanediyl; R¹³ is hydrogen, C₁₋₆alkyl, C₁₋₆alkylcarbonyl,hydroxyC₁₋₆alkyl, aryl or arylC₁₋₆alkyl; R¹⁴ is hydrogen, C₁₋₆alkyl,aryl or arylC₁₋₆alkyl; R¹⁵ is hydrogen, C₁₋₆alkyl, C₁₋₆alkylcarbonyl,aryl or arylC₁₋₆alkyl; R⁴ is a radical of formula

wherein R¹⁶ is hydrogen, halo, aryl, C₁₋₆alkyl, hydroxyC₁₋₆alkyl,C₁₋₆alkyloxyC₁₋₆alkyl, C₁₋₆alkyloxy, C₁₋₆alkylthio, amino, mono- ordi(C₁₋₄alkyl)amino, hydroxycarbonyl, C₁₋₆alkyloxycarbonyl,C₁₋₆alkylthioC₁₋₆alkyl, C₁₋₆alkylS(O)C₁₋₆alkyl orC₁₋₆alkylS(O)₂C₁₋₆alkyl; R¹⁷ is hydrogen, C₁₋₆alkyl,C₁₋₆alkyloxyC₁₋₆alkyl, arylC₁₋₆alkyl, trifluoromethyl ordi(C₁₋₄alkyl)aminosulfonyl; R⁵ is C₁₋₆alkyl, C₁₋₆alkyloxy or halo; arylis phenyl, naphthalenyl or phenyl substituted with one or moresubstituents each independently selected from halo, C₁₋₆alkyl,C₁₋₆alkyloxy or trifluoromethyl; with the proviso that that when R¹⁶ isbound to one of the nitrogen atoms in the imidazole ring of formula(c-1) or (c-2), R¹⁶ is hydrogen, aryl, C₁₋₆alkyl, hydroxyC₁₋₆alkyl,C₁₋₆alkyloxyC₁₋₆alkyl, C₁₋₆alkyloxycarbonyl, C₁₋₆alkylS(O)C₁₋₆alkyl orC₁₋₆alkylS(O)₂C₁₋₆alkyl.
 2. The method according to claim 1 wherein saidabnormal cell growth the form of a tumor.
 3. The method according toclaim 1 wherein the compound is5-(3-chlorophenyl)-α-(4-chlorophenyl)-α-(1-methyl-1H-imidazol-5-yl)tetrazolo[1,5-a]quinazoline-7-methanamineor a pharmaceutically acceptable acid addition salt or astereochemically isomeric form thereof.
 4. The method according to claim3 wherein said abnormal cell growth is in the form of a tumor.
 5. Themethod according to claim 2 wherein the tumor is selected from the groupconsisting of lung cancer, pancreatic cancers, colon cancers,hematopoietic tumors of lymphoid lineage, myeloid leukemias, thyroidfollicular cancer, myelodysplastic syndrome (MDS), tumors of mesenchymalorigin, melanomas, teratocarcinomas, neuroblastomas, gliomas, benigntumor of the skin, breast carcinoma, kidney carcinoma, ovary carcinoma,bladder carcinoma and epidermal carcinoma.
 6. The method according toclaim 5 wherein the tumor is selected from the group consisting ofadenocarcinoma, exocrine pancreatic carcinoma, colon adenocarcinonla,colon adenoma, acute lymphocytic leukemia, B-cell lymphoma, Burkitt'slymphoma, acute myelogenous leukemia (AML), fibrosarcomas,rhabdomyosarcomas, and keratoacanthomas.
 7. The method according toclaim 4 wherein the tumor is selected from the group consisting of lungcancer, pancreatic cancers, colon cancers, hematopoietic tumors oflymphoid lineage, myeloid leukemias, thyroid follicular cancer,myelodysplastic syndrome (MDS), tumors of mesenchymal origin, melanomas,teratocarcinomas, neuroblastomas, gliomas, benign tumor of the skin,breast carcinoma, kidney carcinoma, ovary carcinoma, bladder carcinomaand epidermal carcinoma.
 8. The method according to claim 7 wherein thetumor is selected from the group consisting of adenocarcinoma, exocrinepancreatic carcinoma, colon adenocarcinoma, colon adenoma, acutelymphocytic leukemia, B-cell lymphoma, Burkitt's lymphoma, acutemyelogenous leukemia (AML), fibrosarcomas, rhabdomyosarcomas, andkeratoacanthomas.